DESCRIPTION: (Investigator's abstract) The long-term objective of this research is to determine the in vivo role of coagulation factors, specifically that of Factor VII (FVII). FVII is generally accepted to play a key role in the initiation of coagulation following vascular injury. The overall goal of the proposed research is examine in detail the initiation of coagulation and hemostatic response after vascular injury and inflammatory challenge in the presence or absence of FVII. The approach to the problem is to utilize recently generated FVII- and FIX-deficient mice. FVII(-/-), FXI(-/-), FVII(-/-)/FXI(-/-) and wild-type mice will be examined after vascular injury. Thrombus formation and fibrin deposition will be monitored. This strategy will reveal the critical roles of FVII by identifying which processes are impaired in the absence of FVII. Furthermore, by genetically blocking FVII-initiated coagulation, it will be possible to identify whether and to what extent FXI contributes to the initiation of coagulation and thrombus formation. In addition, several elements in the coagulation pathway have been shown to affect embryogenesis. While FVII-deficient and FXI-deficient mice develop normally, it is proposed to determine if simultaneous knockout of both known coagulation initiating pathways result in embryonic lethality. Normal development of FVII/FXI-deficient double gene deletions might suggest alternative mechanisms to initiate the coagulation cascade during embryogenesis. Coagulation is involved in many normal and pathophysiological conditions including hemostasis, thrombosis, inflammation, atherosclerosis, and cancer. The proposed research will contribute to our understanding of elements contributing to coagulation initiation in vivo.